The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance

Abstract

Gliomas are a diverse group of brain tumors comprised of malignant cells ('tumor' cells) and non-malignant 'normal' cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both 'tumor' and 'normal' cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell-cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that 'vesiculome' data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.

Keywords: biomarkers; extracellular vesicles; glioma; liquid biopsy; tumor microenvironment.

Figure 1

Schematic of extracellular vesicle (EV) biogenesis and signaling between neighboring cells. Generation of EVs from a host cell, depicting small (sEV; 40–200 nm), and medium to large (m/lEV; 0.2–1 µm) EVs and apoptotic bodies (1–5 µm). sEVs find their origin in the early endosomal compartment which give rise to multivesicular bodies (MVBs). MVBs fuse with the plasma membrane to secrete sEVs. Biogenesis of sEVs can occur via the endosomal sorting complex related to transport (ESCRT)-dependent pathway or ESCRT-independent pathway. Release of sEVs involves proteins such as RabGTPases (e.g., Rab11, Rab35, Rab27a/27b). Cargo in MVBs fated for degradation are processed via lysosomes. m/lEVs are released by budding of the plasma membrane regulated by proteins including Arf6 and RhoA GTPase, while dying cells undergo blebbing and form cell protrusions to release apoptotic bodies. Exomeres (~35 nm) are also released by cells via unknown mechanisms. A magnified sEV is presented on the right, demonstrating commonly found sEV cargo (DNA, messenger RNA (mRNA), microRNA (miRNA), non-coding RNA (ncRNA), long non-coding RNA (lncRNA), proteins, enzymes, heat shock proteins). Recipient cells internalize sEVs via endocytosis.

Figure 2

Schematic of EV-mediated cell–cell interactions in the healthy and tumorigenic brain. Normal brain (left panel) and brain tumor microenvironment (right panel). In a healthy state, EVs released by normal neural cells (neural stem cells (NSCs), neurons, oligodendrocytes, astrocytes), inflammatory cells (microglia) and endothelial cells promote cell–cell interactions, which contribute toward the formation of an intricate neural network (left side; magnified panel). In a tumorigenic state, the tumor microenvironment is a complex ecosystem of tumor cells intricately knit together with ‘normal’ brain cells. Tumor–tumor homotypic interactions and tumor–‘normal’ cell heterotypic interactions can be mediated via EVs secreted in the tumor microenvironment. Cell-specific EVs are represented as small spheres with the same color as the cell that releases them.